Field of the Invention
The invention relates to mass spectrometers with tandem ion mobility analyzers, in particular comprising built-in trapped ion mobility spectrometry (TIMS) analyzers, and corresponding methods for separating ions according to their mobility for detailed substance analyses.
Description of the Related Art
U.S. Pat. No. 7,838,826 B1 (M. A. Park, 2008) presents a small ion mobility analyzer/spectrometer which has become known under the acronym “TIMS” analyzer/spectrometer (TIMS=trapped ion mobility spectrometry). The terms ion mobility analyzer and spectrometer are used interchangeably here. A TIMS analyzer comprises a gas flow that drives ions against a counter-acting electric field barrier such that the ions are at first trapped along the axis of the TIMS analyzer. The ions are confined in the radial direction by an electric RF field. After transferring ions from an ion source to the electric field barrier, the height of the electric field barrier or the gas velocity is adjusted such that ion species are released from the electric field barrier in the sequence of their mobility.
Commonly, the length of the ion mobility separation unit of a TIMS analyzer amounts to about five centimeters only. In a small tube with an inner diameter of about eight millimeters, a radial RF quadrupole field is generated to hold ions near to the axis. A gas flow inside a tube drives ions entrained in the gas flow against a ramped counter-acting electric DC field barrier where the ions are trapped and separated according to their mobilities at locations on the field ramp at which the friction force of the moving gas equals the counter-acting force of the electric DC field on the ramp. After loading the TIMS with ions, the height of the electric DC field barrier is decreased; this scan releases the ion species in the sequence of their mobility. Unlike many other trials to build small ion mobility spectrometers, the small device by M. A. Park has already achieved, with reduced scan speeds, ion mobility resolutions up to Rmob=400, which is extraordinarily high.
FIG. 1 outlines schematically a common TIMS analyzer and its operation. Entrained by a gas (7), ions (6) from an electrospray ion source (not shown) are introduced via capillary (8) into a first chamber of a vacuum system. A repeller plate (9) drives the ions (6) into an entrance funnel (10) of the mobility analyzer. Ion funnels (10, 12) usually are built as a stack of apertured diaphragms the openings of which taper to smaller diameters thus forming an inner volume in the shape of a funnel. Two phases of an RF voltage are applied alternately to the diaphragms to build up a pseudopotential which keeps the ions away from the funnel walls. The ions are driven to and through the narrow end of the first funnel (10) into the TIMS tube (11) by an axial gas flow (14) and optionally by an additional DC potential gradient along the diaphragms.
The axial gas flow (14) through the TIMS tube (11) is laminar and shows, in radial direction, a substantially parabolic velocity distribution. Nitrogen may serve as a preferred gas. The vacuum conditions around the TIMS tube (11) are chosen such that the maximum gas velocity amounts to about 100 to 150 meters per second, at a pressure of a few hectopascals. This velocity is only achieved near the axis. Further off axis, the velocity is considerably smaller, as indicated by the arrows (14) in FIG. 1.
The first funnel (10) guides the ions into the TIMS tube (11) forming a tunnel with internal RF quadrupole field in radial direction. The TIMS tunnel (11) comprises a stack of thin electrodes with central holes which form a circular tube arranged around the z-axis of the device. The thin electrodes are separated by insulating material closing the gaps between the electrodes around the tube. The electrodes of the TIMS tube (11) are segmented into quadrants (1, 2, 3, 4), to allow for the generation of a radially confining quadrupolar electric RF field inside. The quadrants (1, 2, 3, 4) of the tube electrodes are shown at the top of FIG. 1 with equipotential lines of the quadrupolar RF field inside the tube at a given time. It should be mentioned here that the design of a quadrupole tunnel does not necessarily consist of metal electrode sheets; there are a lot of different possibilities including stacked PCB boards or even a rolled PCB board with printed electrodes.
Inside the TIMS tunnel (11), the ions are blown by the gas flow (14) against an axial electric DC field barrier. In the center part of FIG. 1, the profile of the axial electric DC field barrier is shown for three phases of a scan. Between z locations (20) and (23), the electric DC field increases linearly, generated by a quadratically increasing electric potential. Between z locations (23) and (24), the electric DC field remains constant, forming a plateau of the electric DC field barrier, generated by a linear increase of the electrical potential. In a simple device, for instance, the complete field profile can be generated by a single voltage, applied to the diaphragm electrode at location (24), and divided by precision resistors along the diaphragm electrodes of the TIMS tube (11). The resistors between location (20) and (23) increase linearly, the resistors between (23) and (24) have equal resistance. In more complex devices, non-linear field electric field profiles may be generated, even adjustable DC field profiles, e.g. by digital-to-analog converters (DAC).
The operation of the TIMS analyzer starts with an “ion accumulation phase”, accumulating ions on the uppermost electric DC field ramp of the diagram. A voltage difference on the order of 300 volt produces the electric DC field barrier. The ions are blown by the gas flow, symbolically indicated by the arrows (16), against the electric DC field barrier and are stopped there because they cannot surmount the electric DC field barrier. It should be noted that the arrows (16) represent the maximum gas velocity of the parabolic gas velocity distribution (14) within the tube. The ions are accumulated on the rising edge of the electric DC field between locations (20) and (23), where ions of low mobility (mainly heavy ions with large collision cross section) gather in the high field near the upper end of the field ramp, whereas ions of high mobility gather in the low field near the foot of the ramp. The size of the dots represents the abundance of the ions of distinct ion mobility, indicating the strength of the space charge. In the subsequent “scan phase”, the supply voltage for the electric DC field barrier is steadily decreased, and ions of increasing mobility can escape towards an ion detector, particularly to a mass analyzer operating as ion detector. In the bottom of the figure, the resulting ion current of the released ion species is shown. The measured total ion current curve i=f(t) presents directly an ion mobility spectrum from low ion mobilities to high ion mobilities.
Regarding the theoretical basis of TIMS, see the research article “Fundamentals of Trapped Ion Mobility Spectrometry”, K. Michelmann, J. A. Silveira, M. E. Ridgeway and M. A. Park, J. Am. Soc. Mass Spectrom., (2015) 26: 14-24 (published online: 21 Oct. 2014).
Improvements of the scan modes for TIMS analyzers have been made by application of non-linear scans to achieve a linear mobility scale, a constant resolution along the mobility scale, or a temporal zoom (M. A. Park et al., U.S. Pat. No. 8,766,176 B2). Furthermore, U.S. patent application Ser. No. 15/341,250 (M. A. Park and O. Raether) describes a spatial zoom.
The ion mobility resolution Rmob depends on the scan speed. FIG. 3 presents a typical function of the ion mobility resolution versus scan duration. The lower the scan speed, the higher the resolution. As already mentioned, ion mobilities of Rmob=400 have been achieved with the comparably small devices, using slow scans. Since the ions generated in the ion source are lost during the scan phases, the duty cycle (or the utilization rate of the ions) depends on the ratio of the accumulation time ta to the scan time ts.
A TIMS analyzer with parallel ion accumulation is described in U.S. patent application Ser. No. 14/614,456 (“Trapping Ion Mobility Spectrometer with Parallel Accumulation”, M. A. Park and M. Schubert); it improves the utilization of the ions from the ion source to nearly 100%. TIMS with parallel accumulation does in fact collect and separate by ion mobility all ions of the ion source without any losses of ions, as long as space charge effects do not impair further collection of ions. TIMS with parallel ion accumulation further provides the unique possibility to prolong the ion accumulation duration to find more detectable ion species, thereby even increasing the ion mobility resolution by a corresponding prolongation of the scan time. The ions are collected in an accumulator unit, preferably almost identical to the scanning unit, at a ramp of an electric DC field barrier such that they get spatially separated by their ion mobility along the ramp. Therefore, the accumulated ions are less influenced by space charge than in other types of accumulator units. Of greatest importance, however, is the unique feature of a TIMS analyzer that a longer accumulation period permits to increase the mobility resolution by choosing correspondingly longer mobility scan durations, e.g. 100 milliseconds scan duration with an ion mobility resolution of Rmob=75 instead of 20 milliseconds scan duration with Rmob=30. As a consequence of the higher number of ions collected and the better ion mobility resolution, more ion species can be detected and measured. Once an ion mobility scan is completed (optionally after twenty to some hundred milliseconds), the accumulated ions are transferred (in about a millisecond) from the accumulation unit to the scanning unit, and the next ion mobility scan can be started. In total, a skilled practitioner will appreciate that it will be possible to achieve a measurement rate of 300 to 450 ion species per second. If TIMS with parallel ion accumulation is installed in tandem mass spectrometer (MS/MS instrument) an MS-MS instrument, 300 to 450 characteristic fragment ion spectra per second may be measured quantitatively.
The major challenge with TIMS (as with other trapping spectrometers) is space charge. Some improvements for higher amounts of stored ions in selected regions of ion mobility, particularly for ions of low ion mobility, are given in U.S. Pat. No. 9,304,106 B1 (M. A. Park and O. Raether, “High Duty Cycle Trapping Ion Mobility Spectrometer”). The higher loading capacity is based on non-linear electric DC field ramps, with flatter field ramps for ion species of interest, in order to diminish the effect of space charge for these ion species. But for precise ion mobility analyses of low abundant ion species in complex mixtures the influence of the space charge is still too high.
There is still a need for a method to analyze precisely the mobility of low abundant ions in the nearby presence of high abundant ions with high amount of space charge.